A fundamental challenge in neuroscience is understanding of how major brain areas operate together as a system to support high level cognitive functions. In particular, one system of great importance to the understanding of mental disorders involves the prefrontal cortex (PFC) and the medial temporal lobe (MTL) that each contribute to high level functions in memory and cognition. In recent years, there has been significant progress in revealing the individual functions of areas within the PFC and MTL, and some successes in showing that these areas work together. However, there is a paucity of knowledge about the mechanisms by which PFC and MTL interact in the service of memory and cognition. Here we bring together a group of investigators who have led research on PFC and MTL, or both, using diverse approaches and different species. We have collaborated to develop an hypothesis of PFC-MTL interactions and aim to integrate our strengths towards revealing the mechanisms of that interaction, and in so doing, pioneer a true systems level understanding of memory and cognition. Our strategy combines theories of PFC and MTL function generated by our group with coordinated experimental analyses that converge on a common behavioral paradigm for exploring encoding and retrieval operations in context-guided associative memory. Experimental projects will examine how PFC and MTL areas contribute individually and interactively, using diverse and intersecting approaches: in humans, using both neuropsychological studies of brain damaged individuals and fMRI on normal human subjects, in monkeys using neurophysiological studies of single neuron activity and local field potentials, in rats using combined neurophysiological and reversible inactivation studies of non-spatial and spatial memory. The findings will be integrated in two key ways, by direct comparison of different data modalities through an Analysis Core and by convergence into a computational model that provides a comprehensive and unified account of PFC-MTL interactions. The Center will also pursue several directly related educational, dissemination, and outreach goals. PUBLIC HEALTH RELEVANCE: PFC and MTL areas are implicated in a broad range of mental disorders. Moreover, it has become increasingly clear that aspects of mental disorders reflect a breakdown of network functions of the PFC-MTL system. Correspondingly, characterization of PFC-MTL interactions is fundamental to understanding the origins of mental disorders and to developing therapies that influence network-level information processing.